Magnetic Resonance Imaging (MRI) is a powerful diagnostic method in which three-dimensional images in vivo of body tissues are obtained based on the distribution of water in these tissues. MRI contrast agents administered prior to imaging alter the relaxation times of protons in their vicinity enhancing specific features of an image. MRI contrast agents improve the sensitivity and utility of MRI diagnostics. See: The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging; Merbach, A. E., Toth, E., Eds.; John Wiley & Sons, Ltd.: New York, 2001; Tweedle, M. F.; Kumar, K. Top. Biol. Inorg. Chem. 1999, 2, 1-43; Reichert, D. E.; Lewis, J. S.; Anderson, C. J. Coord. Chem. Rev. 1999, 184, 3-66; and Allen, M. J.; Meade, T. J. Met. Ions Biol. Syst. 2004, 42, 1-38.
Raymond and coworkers have reported hydroxypyridonate (HOPO)-based Gd(III) chelates that are more effective at enhancing the contrast of MR images (Raymond, K. N.; Pierre, V. C. Bioconjugate Chem. 2005, 16, 3-8. and Xu, J.; Franklin, S. J.; Whisenhunt, D. W., Jr.; Raymond, K. N. J. Am. Chem. Soc. 1995, 117, 7245-7246. U.S. published patent application 2005/0008570 (Raymond et al.), published Jan. 13, 2005, reports hydroxypyridonate and hydroxypyrimidinone chelating agents including Gd(III) complexes for use as MRI contrast agents.
The strength of Gd(III)-based contrast agents can be improved by increasing the number of coordinated water molecules, optimizing the water exchange rate between bound and bulk water molecules, increasing the rotational correlation time, or increasing the number of Gd(III) ions per molecule (Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Chem. Rev. 1999, 99, 2293-2352; Uzgiris, E. E.; Cline, H.; Moasser, B.; Grimmond, B.; Amaratunga, M.; Smith, J. F.; Goddard, G. Biomacromolecules 2004, 5, 54-61; Aime, S.; Botta, M.; Terreno, E. Adv. Inorg. Chem. 2005, 57, 173-237.) The HOPO-based agents have an increased number of water molecules in the innersphere environment and a near optimal water exchange rate; together, these features lead to a higher relaxivity (Xu, J.; Franklin, S. J.; Whisenhunt, D. W., Jr.; Raymond, K. N. J. Am. Chem. Soc. 1995, 117, 7245-7246.) Increasing the rotational correlation time can further improve these agents (Pierre, V. C.; Botta, M.; Raymond, K. N. J. Am. Chem. Soc. 2005, 127, 504-505.)
This invention relates to polymeric HOPO-based metal chelating agents and metal chelates generated by using ring-opening metathesis polymerization (ROMP). Multiple HOPO-based chelating groups are integrated into structural units that constitute the backbone of the polymer formed upon ROMP. Using this technique highly sensitive and tunable contrast agents can be made through incorporation of multiple HOPO-based Gd(III) chelates into an easily functionalizable macromolecule.
Polymers comprising one or more Gd(III) complexes have been made which function as MRI contrast agents with extraordinary sensitivity and versatility. Additionally, the utility of contrast agents can be increased by equipping them with targeting moieties or fluorescent probes.
ROMP is an ideal polymerization method for this purpose because it can yield polymers of well-defined length. See: Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29 and U.S. Pat. No. 5,880,231 (Grubbs et al.). Additionally, ROMP is amenable to the generation of polymers with multiple sites for functionalization, allowing for the synthesis of multimodal and targeted contrast agents. See: Strong, L. E.; Kiessling, L. L. J. Am. Chem. Soc. 1999, 121, 6193-6196 and Pontrello, J. K.; Allen, M. J.; Underbakke, E. S.; Kiessling, L. L. J. Am. Chem. Soc. 2005, 127, 14536-14537; U.S. Pat. No. 6,291,616 (Kiessling et al.); International published application WO01/71309 (Kiessling et al.). U.S. Pat. No. 6,271,315 (Kiessling et al.) relates to methods for making ROMP-derived polymers employing functionalized carbene catalysts and/or functionalized capping agents.